Sleep and Psychiatric Disorders
Andrew D. Krystal
Sleep and psychiatric disorders are related in important and complex ways. Sleep problems are highly prevalent among individuals with psychiatric disorders. In this regard, sleep problems are among the defining features of some psychiatric conditions. Although it was long commonly held that these disturbances of sleep were symptoms of the associated psychiatric disorders, the available data suggest that the relationship between sleep disturbance and psychiatric disorders is more complex. Sleep disturbances can have important effects on the course and treatment response of the associated psychiatric conditions, suggesting that these sleep disorders have independent importance and merit specific therapeutic attention. It is also the case that some sleep disorders are associated with psychiatric symptoms, and some sleep conditions are associated with an increased risk for experiencing episodes of psychiatric disorders.
Further complexity in the relationship emerges when one considers the treatments for psychiatric disorders and sleep disorders. Some therapies are used to treat both sleep disorders and psychiatric disorders, including antidepressant, anxiolytic, antipsychotic, and stimulant medications (1, 2, 3, 4 and 5). In addition, treatments for psychiatric conditions may lead to disturbances of sleep, and, at the same time, treatments for sleep disorders may predispose individuals to the development of psychiatric disturbances (6,7). It is also the case that sleep deprivation may be therapeutic for those with some psychiatric conditions and may exacerbate other psychiatric conditions (8).
The relationships among sleep and psychiatric disorders have both clinical and scientific implications. In this chapter, we review the current literature on the important sleep-related issues for each of a series of psychiatric disorders (major depressive disorder [MDD], bipolar disorder [BPD], schizophrenia, generalized anxiety disorder [GAD], and alcoholism) and discuss the implications for both research and clinical practice.
MAJOR DEPRESSIVE DISORDER
MDD has a lifetime prevalence of 10% to 25% in women versus 5% to 12% in men (9). The diagnostic criteria require the presence of five of nine criteria symptoms over a period of at least 2 weeks where one of the five symptoms has to be either depressed mood or loss of interest or pleasure. The nine symptoms included in the diagnostic criteria are (i) depressed mood, (ii) loss of interest or pleasure in activities, (iii) change in appetite, (iv) insomnia or hypersomnia, (v) psychomotor agitation or retardation, (vi) fatigue, (vii) feelings of worthlessness or guilt, (viii) poor concentration and difficulty making decisions, and (ix) suicidal ideation.
It is important to note that sleep difficulties (insomnia or hypersomnia) are among the diagnostic criteria for MDD and, accordingly, are found in as many as 90% of patients with this condition (10). The sleep complaints of those with MDD include trouble falling asleep, trouble staying asleep, waking too early in the morning with an inability to return to sleep, poor sleep quality, nightmares, and daytime sleepiness.
There also appear to be characteristic changes in the polysomnogram in those with major depression. In addition to disturbed sleep, as evidenced by increased sleep latency, frequent wakefulness, and early morning awakening (11, 12, 13 and 14), a number of studies have reported that alterations in rapid eye movement (REM) sleep
are associated with major depression; most commonly, this has been a reduction in the time to the onset of REM sleep (shortened REM latency) (11,15, 16, 17, 18, 19, 20, 21, 22, 23 and 24). An increase in the number of eye movements per minute of REM sleep (REM density) has also been reported (13,25, 26 and 27), as has an increase in the percentage of REM sleep (13,14,23) and a longer duration of the first REM period (14,28,29). A decreased amount of slow-wave sleep (SWS) has also been reported in some studies (13,14,19,24,30) but not others (22,30,31).
are associated with major depression; most commonly, this has been a reduction in the time to the onset of REM sleep (shortened REM latency) (11,15, 16, 17, 18, 19, 20, 21, 22, 23 and 24). An increase in the number of eye movements per minute of REM sleep (REM density) has also been reported (13,25, 26 and 27), as has an increase in the percentage of REM sleep (13,14,23) and a longer duration of the first REM period (14,28,29). A decreased amount of slow-wave sleep (SWS) has also been reported in some studies (13,14,19,24,30) but not others (22,30,31).
It is important to appreciate that the significance of these changes in sleep for the pathophysiology of MDD remains uncertain. There is reason to believe that some of these changes, including REM density and decreased sleep efficiency, might be state markers for episodes of MDD, as they are more prominent in the acute stages of a depressive episode (32, 33 and 34). However, reduced REM latency and decreased SWS may be present in those prone to mood disorders even when not in an episode of depression and may persist after the symptoms of MDD have remitted with therapy, suggesting that they may be of the nature of trait markers for the predisposition to MDD (32,35, 36, 37 and 38). More work is needed to better elucidate the pathophysiologic implications of sleep changes in those with MDD; however, there is evidence that these markers are of relatively limited clinical utility. Although polysomnographic (PSG) alterations such as shortened REM latency reliably distinguish depressed individuals from healthy controls, they appear not to be specific markers of depression because they may occur in patients with other psychiatric disorders (20). Generally, in clinical contexts, it is much more important to be able to distinguish individuals with depression from those with other psychiatric conditions.
Disturbances of sleep in those with major depression is well established. However, it is less widely appreciated that disturbances of sleep may have an important impact on MDD. Depression appears to be more likely in those with sleep disorders. MDD is found in 20% to 31% of those with insomnia and in 25% of those with hypersomnia but only in 1% to 2.7% of controls without sleep disorders (39, 40 and 41). Further, insomnia has been found to be a predictor of an increased risk for the development of new-onset MDD in several longitudinal studies (40,42,43).
Insomnia is not only a risk factor for the development of MDD—the presence of insomnia appears to have a substantive impact on the course and treatment response of those with major depression. For many years, insomnia occurring in the setting of major depression was viewed as a “secondary” symptom of MDD that was without independent consequences and that resolved with antidepressant therapy along with the other symptoms of MDD and therefore did not merit specific therapy (44). There is now a preponderance of evidence that this view is incorrect. Disturbed sleep frequently fails to resolve with antidepressant treatment, persisting in 20% to 44% (45,46); this residual insomnia has been associated with an increased risk of relapse of MDD as well as diminished daytime concentration, daytime sleepiness, and ability to perform daily activities (47,48). In addition, at least 16 studies have reported an association of sleep disturbance and either suicidal ideation or completed suicide, and in many cases, this relationship persisted after taking into account depression severity (49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 and 63). Poor sleep is also associated with slower MDD response and lower remission rates (64, 65, 66 and 67). Poorer sleep among those with MDD has also been found to be associated with poorer quality of life after controlling for depression severity (68).
Further evidence for the independent importance of sleep disturbance in those with MDD and the importance of targeting treatment specifically to these sleep problems are studies demonstrating that providing insomnia therapy along with antidepressant therapy improves not only sleep but also the depression response. In a study where the insomnia agents lormetazepam, flunitrazepam, or placebo were given adjunctively to antidepressant medication (either nortriptyline
or maprotiline), those given lormetazepam experienced greater improvement in depression than subjects receiving placebo (69). The administration of eszopiclone 3 mg along with fluoxetine not only improved sleep compared with placebo and fluoxetine but also led to more rapid and greater improvement in depression and a greater percentage of depression responders and remitters (70,71). Lastly, subjects receiving cognitive behavioral therapy for insomnia along with escitalopram had a greater depression remission rate than those administered a control behavioral intervention along with escitalopram (62% vs. 33%) (72). These studies suggest that failing to administer efficacious treatment for insomnia may lead to an unnecessary increase in the duration and degree of impairment and disability of those treated for MDD. Additional studies are needed to better define the relationship between insomnia therapy and antidepressant response and to determine if insomnia therapy decreases the risks of suicide in those with MDD and/or decreases the risk of relapse.
or maprotiline), those given lormetazepam experienced greater improvement in depression than subjects receiving placebo (69). The administration of eszopiclone 3 mg along with fluoxetine not only improved sleep compared with placebo and fluoxetine but also led to more rapid and greater improvement in depression and a greater percentage of depression responders and remitters (70,71). Lastly, subjects receiving cognitive behavioral therapy for insomnia along with escitalopram had a greater depression remission rate than those administered a control behavioral intervention along with escitalopram (62% vs. 33%) (72). These studies suggest that failing to administer efficacious treatment for insomnia may lead to an unnecessary increase in the duration and degree of impairment and disability of those treated for MDD. Additional studies are needed to better define the relationship between insomnia therapy and antidepressant response and to determine if insomnia therapy decreases the risks of suicide in those with MDD and/or decreases the risk of relapse.
These studies speak to the potential impact on MDD of treatments for insomnia. There is also a literature documenting that treatments for MDD impact sleep. A number of antidepressants affect sleep architecture, as noted in studies obtaining PSG data. In this regard, the most important finding is that many antidepressants are suppressors of REM sleep (73, 74 and 75). This has been observed with monoamine oxidase inhibitors, tricyclic antidepressants, electroconvulsive therapy (ECT), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs) (20,76, 77, 78 and 79). These observations considered in light of the evidence that REM latency is shortened in MDD and the percentage of REM and frequency of eye movements in REM is increased led to the hypothesis that REM suppression may be needed in order to achieve an antidepressant response. However, the existence of agents with established antidepressant efficacy that lack REM suppression (bupropion, nefazodone, mirtazapine, trazodone) suggests that REM suppression is not a necessary attribute of antidepressant therapies (80). Some of the antidepressants that do not appear to suppress REM sleep, including nefazodone, trazodone, and mirtazapine, have been found in at least some studies to increase the amount of SWS and increase in electroencephalographic delta activity during non-REM sleep (81, 82, 83, 84, 85 and 86). Some antidepressants also have therapeutic effects on sleep onset and/or maintenance and, as a result, are frequently used “off-label” for the treatment of insomnia, though in most cases they are administered in dosages lower than those used to treat depression. The antidepressants most commonly used in this setting are trazodone, mirtazapine, amitriptyline, and doxepin (3). Data supporting a sleep onset and/or maintenance effect for a number of agents derive from studies carried in depressed patients, primary insomnia patients, or healthy controls with amitriptyline, doxepin, and trimipramine, and mirtazapine (85,87, 88, 89, 90, 91, 92, 93, 94 and 95).
A further sleep-related consideration related to depression treatment is that many antidepressants may cause or exacerbate the sleep disorders of restless legs syndrome and periodic movements of sleep (96). Antidepressants that are particularly likely to be associated with these conditions based on the published literature are SSRIs, SNRIs, and mirtazapine (96,97).
Perhaps the most intriguing treatment-related issue linking sleep and depression is the fact that sleep deprivation appears to have robust antidepressant effects. In fact, a single night of sleep deprivation has been found to be associated with antidepressant response rates of 50% in some studies and higher response rates in others (98, 99 and 100). Notably, sleep deprivation is similar to ECT (the most effective treatment known for major depression) and unlike antidepressant medications in that it is more effective for those with greater depression severity (101,102). Despite this promise, there is a major limitation to the clinical utility of sleep deprivation in the treatment of MDD—the limitation that the antidepressant
effect of sleep deprivation generally disappears once the treated individual sleeps, even for a brief period of time (100,103). The only exception to this may be chronic deprivation of REM sleep. A study carried out in the 1970s illustrated that chronic REM deprivation (3 weeks) is also an effective antidepressant therapy where a relatively gradual improvement in depression occurs that persists following recovery sleep (104). However, this study has not been successfully replicated, and chronic REM deprivation appears not to have been implemented to any significant degree. Some have attempted to implement a sleep phase advance and other manipulations in order to augment total sleep deprivation as an antidepressant (105,106). However, sleep deprivation remains an intriguing but rarely implemented antidepressant therapy.
effect of sleep deprivation generally disappears once the treated individual sleeps, even for a brief period of time (100,103). The only exception to this may be chronic deprivation of REM sleep. A study carried out in the 1970s illustrated that chronic REM deprivation (3 weeks) is also an effective antidepressant therapy where a relatively gradual improvement in depression occurs that persists following recovery sleep (104). However, this study has not been successfully replicated, and chronic REM deprivation appears not to have been implemented to any significant degree. Some have attempted to implement a sleep phase advance and other manipulations in order to augment total sleep deprivation as an antidepressant (105,106). However, sleep deprivation remains an intriguing but rarely implemented antidepressant therapy.
Thus, there are many important relationships between sleep and MDD. From a research point of view, important questions remain about the extent to which alterations in sleep might be pathophysiologically related to the development and/or recurrence of MDD and how they may increase the risk for suicidality and affect the response to therapy. From the point of view of clinical practice, the most important message that emerges from the available literature is the need to assess for sleep problems in patients with MDD and to target effective therapy to these sleep problems.
BIPOLAR DISORDER
BPD is less common than MDD, having a lifetime prevalence of only 0.4% to 1.6% in both men and women (9). The DSM-IV-TR criteria for BPD require at least one manic episode, which is defined by elevated or irritable mood accompanied by at least three associated symptoms that could include (i) grandiosity, (ii) decreased sleep need, (iii) pressured speech, (iv) flight of ideas, (v) easy distractability, (vi) increased goal-directed activity, and (vii) impulsivity (9).
As with MDD, the diagnostic criteria for mania include a sleep-related symptom. In this case, it is a decreased need for sleep (107). It is important to note that a decreased need for sleep is, in theory, very different from insomnia. Insomnia is defined as experiencing impairment due to the inability to sleep the amount needed to achieve full restoration from sleep when given an adequate opportunity to do so (9). In contrast, decreased need for sleep implies that one is able to decrease the usual amount of sleep to some degree without experiencing any impairment. This does not mean that manic patients do not experience difficulty falling and staying asleep, as generally accompanies insomnia. Whether they do would likely depend on whether they attempt to sleep more than needed in order to achieve restoration. In general, a decrease in total sleep time occurs with manic episodes and, consistent with the antidepressant effects of sleep deprivation, it has been hypothesized that this loss of sleep plays an important, and possibly pathophysiologic, role in the evolution of mania. In this regard, it has been proposed that there is a positive feedback loop between sleep loss and mania such that decreased sleep promotes mania in those with BPD, which in turn promotes further loss of sleep (107). Support for this proposition is evidence that depriving BPD patients of sleep has been observed to trigger mania (108, 109 and 110).
The mechanisms by which sleep deprivation might promote mania remain unestablished. However, this point of view has clinical implications in terms of suggesting that the treatment of mania should focus on increasing sleep time. In this regard, there have yet to be any studies assessing the degree to which increasing sleep might be effective in the treatment of mania. However, this issue is somewhat clouded by the fact that the therapies generally administered for the treatment of mania all happen to have significant sedative properties. This begs the possibility that these agents may be effective because they enhance sleep.
Data on sleep during the depressed phase of BPD is relatively limited. However, the available data suggest that reports of hypersomnia are more common in depression occurring in those with BPD than in those with unipolar MDD (111). Despite the complaint of hypersomnia, there does not appear to be evidence of significant sleepiness when assessed objectively (111). Whether diff erent types of therapies are needed to address depression in those with BPD because of their tendency to experience hypersomnia remains unknown.
A few studies have been carried out that have attempted to characterize the PSG sleep pattern during mania in patients with BPD. These studies suggest that the PSG findings are quite comparable to what is observed in MDD (112 and 113). These observations suggest that disorders of mood, MDD, and BPD may have some common underlying pathophysiologic features. However, the fact that many of these features are seen in those with other psychiatric disorders suggests that having associated PSG findings in common may not suggest a specific link between MDD and BPD (20).
Very few studies have been carried out on the sleep effects of the primary treatments for BPD, which include the mood-stabilizing agents lithium, valproic acid, and carbamazepine. A number of antipsychotic agents are also used to treat mania. Their sleep-related effects will be discussed in the following section on schizophrenia. One study has been carried out on the PSG effects of lithium in manic patients, and it was found that it increased SWS, suppressed REM sleep, and increased the latency to REM sleep (114). Lithium has also been associated with the potential to trigger or exacerbate restless legs syndrome (115).
In summary, in BPD patients, mania is linked to a decreased need for sleep and depression by the experience of hypersomnia. An important unresolved research question is whether sleep loss plays an etiologic role in the evolution of mania and the mechanism by which this occurs. Further, even though it is standard practice to administer treatments that promote sleep to address mania, it will be important to define the role that increasing sleep time plays in the treatment of mania and whether mechanisms can be identified to optimize mania therapy. Further work is also needed to determine what role, if any, the PSG features of mania may play in the understanding of mania and its treatment. Lastly, it remains to be determined why BPD patients experience hypersomnia during the depressed phase that is not evident on objective testing and whether there are benefits to targeting treatment to this symptom.
SCHIZOPHRENIA
Schizophrenia has a lifetime prevalence of 0.5% to 1%, with a roughly equal prevalence rate in men and women (9). Schizophrenia is a disorder marked by social and/or occupational dysfunction occurring in the setting of at least 1 month where ≥2 of the following occur: (i) delusions, (ii) hallucinations, (iii) disorganized speech, (iv) disorganized behavior, and (v) loss of motivation, flat affect, or alogia (9).
As is evident from the definition, disturbance of sleep is not a cardinal feature of schizophrenia. However, the available evidence suggests that patients with schizophrenia frequently report disturbed sleep in terms of problems falling asleep, problems staying asleep, or poor sleep quality (116, 117, 118, 119 and 120)
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